, Denise A. Yardley , Adam Brufsky , Hope S. Rugo , Sandra M. … · 2019. 11. 26. · 1 Baseline Characteristics, Treatment Patterns, and Outcomes in Patients with HER2-Positive

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Baseline Characteristics, Treatment Patterns, and Outcomes in Patients with HER2-Positive Metastatic

Breast Cancer by Hormone Receptor Status From SystHERs

Melody Cobleigh1, Denise A. Yardley2, Adam Brufsky3, Hope S. Rugo4, Sandra M. Swain5, Peter A.

Kaufman6, Debu Tripathy7, Sara A. Hurvitz8, Joyce O’Shaughnessy9, Ginny Mason10, Vincent Antao11,

Haocheng Li12, Laura Chu11, Mohammad Jahanzeb13

1Rush University Cancer Center, Rush University Medical Center, Chicago, IL, USA; 2Breast Cancer

Research Program, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA;

3Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 4Helen Diller

Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA;

5Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA;

6Breast Oncology, Division of Hematology/Oncology, University of Vermont Cancer Center, University of

Vermont Medical Center, Burlington, VT, USA; 7The University of Texas MD Anderson Cancer Center,

Houston, TX, USA; 8David Geffen School of Medicine, University of California Los Angeles, Los Angeles,

CA, USA; 9Department of Medical Oncology, Baylor University Medical Center, Texas Oncology and US

Oncology, Dallas, TX, USA; 10Inflammatory Breast Cancer Research Foundation, West Lafayette, IN, USA;

11Genentech, Inc., South San Francisco, CA, USA; 12F. Hoffmann-La Roche, Mississauga, ON, Canada;

13Florida Precision Oncology, a division of 21st Century Oncology, Boca Raton, FL, USA

Correspondence to:

Dr. Melody Cobleigh, Brian Piccolo Professor for Cancer Research

Director, Section of Medical Oncology, Rush University Medical Center

Ste 821, Professional Building 1, 1725 W. Harrison, Chicago, IL 60612

Telephone: 312-942-3324

Research. on February 6, 2021. © 2019 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 26, 2019; DOI: 10.1158/1078-0432.CCR-19-2350

http://www.medschool.pitt.edu/

http://clincancerres.aacrjournals.org/

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Email: [email protected]

Running title: Hormone receptor status in HER2-positive MBC from SystHERs

Keywords: HER2-positive metastatic breast cancer, hormone receptor, HER2-targeted therapy,

prospective patient registry study, treatment patterns

Financial support: The SystHERs study was funded by F. Hoffmann-La Roche/Genentech, Inc.




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CONFLICTS OF INTEREST

Dr Cobleigh has received consulting fees and research funding from F. Hoffmann-La Roche/Genentech.

Dr Yardley has received consulting/advisory fees from Novartis and Genentech; and research funding

from F. Hoffmann-La Roche/Genentech and Novartis.

Dr Brufsky has received consulting fees and travel support from F. Hoffmann-La Roche/Genentech,

Novartis, Pfizer, Sandoz, AstraZeneca, Amgen, and Lilly.

Dr Rugo has received travel support from Merck, Mylan, Puma, Lilly, and Pfizer; and research funding

from F. Hoffmann-La Roche/Genentech, Pfizer, Novartis, Lilly, OBI Pharma, Macrogenics, and Merck.

Dr Swain has received consulting fees from Athenex, Daiichi-Sanyo, Eli Lilly and Company, F. Hoffmann-

La Roche/Genentech, Genomic Health, Inivata, Ltd., Novartis, Pieris Pharmaceuticals, and Tocagen;

research funding from F. Hoffmann-La Roche/Genentech, Pfizer, and Merrimack; non-financial support

from Athenex, Daiichi-Sanyo, Eli Lilly and Company, F. Hoffmann-La Roche/Genentech, Inivata, Ltd.,

Novartis, Pieris Pharmaceuticals, Caris Life Sciences, NanoString Technologies, AstraZeneca, Bristol-

Myers Squibb; and is an Independent Data Monitoring Committee member for AstraZeneca.

Dr Kaufman has received consulting fees and research funding from F. Hoffmann-La Roche/Genentech.

Dr Tripathy has received consulting fees from Pfizer and Novartis, and research funding from Novartis.

Dr Hurvitz has received travel support from Novartis, Lilly, and OBI Pharma; and research funding from

F. Hoffmann-La Roche/Genentech, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Sanofi, Pfizer,

Amgen, OBI Pharma, Puma Biotechnology, Dignitana, Bayer, BioMarin, Lilly, Merrimack, Daiichi-Sankyo,

Immunomedics, Macrogenics, Pieris Pharmaceuticals, and Seattle Genetics.




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Dr O’Shaughnessy has received consulting fees from AbbVie Inc., Agendia, Amgen Biotechnology,

AstraZeneca, Bristol-Myers Squibb, Celgene Corporation, Eisai, Genentech, Genomic Health, GRAIL,

Immunomedics, Heron Therapeutics, Ipsen Biopharmaceuticals, Jounce Therapeutics, Lilly, Merck,

Myriad, Novartis, Ondonate Therapeutics, Pfizer, Puma Biotechnology, F. Hoffmann-La Roche, Seattle

Genetics, and Syndax Pharmaceuticals.

Dr Antao and Ms Chu are employees of Genentech and own stock in F. Hoffmann-La Roche/Genentech.

Dr Li is an employee of F. Hoffmann-La Roche/Genentech.

Dr Jahanzeb has received consulting fees from F. Hoffmann-La Roche/Genentech, and served on a

Scientific Advisory Board and Data and Safety Monitoring Board for Puma.

All authors received non-financial support from F. Hoffmann-La Roche in the form of medical writing

support for this manuscript.

Ms Mason has no additional disclosures.




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TRANSLATIONAL RELEVANCE

Evidence suggests that dual targeting of human epidermal growth factor receptor 2 (HER2) and

hormone receptors (HR) improves progression-free survival in patients with HR-positive, HER2-positive

metastatic breast cancer (MBC). Data from SystHERs, a prospective, observational, US-based registry of

977 patients with HER2-positive MBC enrolled 2012–2016, indicates that 56.2% (385/685) of patients

with HR-positive disease in this real-world setting received first-line HER2-targeted therapy + endocrine

therapy; 34.9% (239/685) received HER2-targeted therapy + chemotherapy + sequential endocrine

therapy. Despite recommendations to consider tumors staining 1%–9% HR-positive as HR-positive,

patients with such tumors received endocrine therapy less commonly than those with 10%–100% HR-

positive-staining tumors and exhibited poorer survival. Future studies should assess whether the

increased implementation of maintenance first-line endocrine therapy following HER2-targeted therapy

and chemotherapy can improve or result in different outcomes in patients with HR-positive, HER2-

positive disease, and whether endocrine therapy improves outcomes in cases with low HR-positivity.




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ABSTRACT

Background

We report treatments and outcomes in a contemporary patient population with human epidermal

growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) by hormone receptor (HR)

status from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs).

Methods

SystHERs (NCT01615068) was an observational, prospective registry study of US-based patients with

newly diagnosed HER2-positive MBC. Endpoints included treatment patterns and clinical outcomes.

Results

Of 977 eligible patients (enrolled from 2012–2016), 70.1% (n=685) had HR-positive and 29.9% (n=292)

had HR-negative disease. Overall, 59.1% (405/685) of patients with HR-positive disease received any

first-line endocrine therapy (with or without HER2-targeted therapy or chemotherapy); 34.9% (239/685)

received HER2-targeted therapy + chemotherapy + sequential endocrine therapy. Patients with HR-

positive versus HR-negative disease had longer median overall survival (OS; 53.0 vs. 43.4 months; hazard

ratio 0.70, 95% confidence interval 0.56–0.87). Compared with patients with high HR-positive staining

(10–100%, n=550), those with low HR-positive staining (1%–9%, n=60) received endocrine therapy less

commonly (64.2% vs. 33.3%) and had shorter median OS (53.8 vs. 40.1 months). Similar median OS (43.4

vs. 40.1 months) was observed in patients with HR-negative versus low HR-positive tumors (1%–9%).

Conclusions

Despite evidence that first-line HER2-targeted therapy, chemotherapy, and sequential endocrine

therapy improves survival in patients with HR-positive, HER2-positive disease, only 34.9% of patients in




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this real-world setting received such treatment. Patients with low tumor HR positivity (1%–9%) had

lower endocrine therapy use and worse survival than those with high tumor HR positivity (10%–100%).




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INTRODUCTION

Breast cancer comprises more than 25% of newly diagnosed cases of cancer in women worldwide (1). Of

women in the United States with metastatic breast cancer (MBC), 14.8% have human epidermal growth

factor receptor 2 (HER2)–positive and hormone receptor (HR)–positive MBC, and 8.9% have HER2-

positive and HR-negative disease (2). Among patients with HER2-positive MBC, clinical outcomes have

been shown to differ between patients with HR-positive versus HR-negative disease. In an observational

study that enrolled patients with HER2-positive MBC from 2007 to 2009, patients with HR-positive

disease had longer median survival than those with HR-negative disease (34.4 vs. 19.8 months) (3).

Data from clinical trials have suggested that dual targeting of HR and HER2 is associated with better

progression-free survival (PFS) in patients with HR-positive, HER2-positive MBC (4–6). Results from

registHER, a registry study of patients with HER2-positive MBC enrolled from 2003 to 2006, showed

improved PFS with the addition of endocrine therapy to first-line trastuzumab + chemotherapy (20.4 vs.

9.5 months with trastuzumab + chemotherapy without endocrine therapy; hazard ratio [HR] 0.53, 95%

confidence interval [CI], 0.42–0.68) and lower risk of death (HR 0.50, 95% CI, 0.36–0.70) in patients with

HR-positive, HER2-positive MBC (7). Furthermore, overall survival (OS) was longer with the use of

sequential (vs. concurrent) chemotherapy and endocrine therapy (HR 0.48, 95% CI, 0.26–0.89).

However, there are limited recent data detailing treatments actually administered to this patient

population in the real world. This gap is notable in light of the US approval of several new HER2-targeted

therapies for MBC, including lapatinib (2007), pertuzumab (2012), and trastuzumab emtansine (T-DM1;

2013). The combination of pertuzumab + trastuzumab + taxane is a current first-line standard of care for

patients with HER2-positive MBC based on results from CLEOPATRA, in which it demonstrated

significantly improved clinical outcomes relative to trastuzumab + taxane alone (8, 9). As clinical trials

supporting US Food and Drug Administration (FDA) approval of modern HER2-targeted agents generally




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did not allow for use of endocrine therapy while patients were on study treatment, additional

contemporary data are needed to understand treatment patterns and outcomes in patients with HR-

positive, HER2-positive MBC within the current treatment landscape.

In addition to the approval of several new HER2-targeted therapies in recent years, the accepted

definition of HR positivity has shifted over the past decade. In 2010, ASCO and the College of American

Pathologists (CAP) proposed a cut-off of ≥1% of cells staining HR-positive (eg, tumor cell

immunoreactivity for the estrogen receptor [ER] and/or progesterone receptor [PR]) to differentiate HR-

positive from HR-negative disease, replacing the previously common threshold of ≥10% (10). Little is

known about the characteristics, treatment patterns, and outcomes of patients with MBC who also have

low HR positivity (1–9%), and whether this patient subgroup resembles those with moderate/high HR

positivity (10–100%) versus HR-negative MBC in the real world.

The Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) was a fully enrolled

(2012–2016), observational, prospective registry study of patients with recently diagnosed HER2-

positive MBC in the United States. Representing a large contemporary population of patients with HER2-

positive MBC, SystHERs is well-suited to characterize the management of patients with HR-positive,

HER2-positive disease in the real-world setting. Here, we report baseline characteristics, treatment

patterns, and clinical outcomes from SystHERs in patients with HR-positive and HR-negative disease,

including subgroups of patients stratified by percentage of HR positivity (low [1%–9%] vs. moderate/high

[10%–100%]), MBC diagnosis type (de novo vs. recurrent), age (<50 years vs. 50–69 years), and race

(black/African American vs. white).

MATERIALS AND METHODS




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Study design and participants

SystHERs (NCT01615068) was a prospective, multicenter, observational cohort study based in the United

States. Patients were assessed and treated per their treating physician’s standard practice. The primary

study endpoint was treatment patterns; secondary endpoints included clinical outcomes. Additional

study design information is included in the published study protocol (11).

At enrollment, eligible patients were aged ≥18 years and had an initial diagnosis of HER2-positive MBC

within 6 months. Written informed consent for the use of medical records was provided by participating

patients. SystHERs was conducted per US FDA regulations, the International Conference on

Harmonisation E6 Guidelines for Good Clinical Practice, the Declaration of Helsinki, and applicable local

laws. Study sites obtained approval of the study protocol by the site’s ethics committee or institutional

review board (IRB). A central IRB was used for sites that did not have an IRB. Although initially planned

to include at least 5 years of follow-up (11), the SystHERs registry was terminated early due to the

sponsor’s decision to prioritize evaluation of new therapies in patients with breast cancer.

Evaluations and follow-up

HER2 status was determined locally by the treating physician based on the primary tumor or biopsy of

recurrence. HR-positive disease was defined based on physician report, as captured on the case report

form. Tumors were defined as HR-positive if any measurement from early breast cancer, MBC, or the

primary breast tumor was recorded as ER-positive and/or PR-positive. In patients with HR-positive

disease, the percentage of HR positivity was defined as the highest percentage of ER-positive or PR-

positive cells. The percentage of ER-positive or PR-positive cells was not reported for patients

considered by local investigators to have HR-negative disease.




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Disease history, previous cancer-related treatment data, and baseline patient and disease characteristics

were collected at enrollment. Treatments for MBC, disease progression, and clinical outcomes were

captured quarterly from patient charts, diagnostic tests, laboratory findings, and clinical notes. Treating

physicians identified metastatic sites at MBC diagnosis and on study. Patients who discontinued the

study were provided the option to participate in quarterly survival follow-up.

Analyses and statistical methods

Key patient cohorts were defined as those with HR-positive versus HR-negative disease. Secondary

subgroups included those stratified by percentage of HR positivity (1%–9% and 10%–100% HR positivity;

i.e., low and moderate/high HR positivity, respectively), MBC diagnosis type (de novo and recurrent

disease, in which de novo MBC was defined as an initial breast cancer diagnosis with distant metastases

observed concurrently, or confirmed within 90 days), age at enrollment (<50 years, 50–69 years, and

≥70 years), and race (black/African American and white).

Median follow-up was calculated as the median observation time from MBC diagnosis to data cutoff.

First-line treatment was defined as any therapy received for MBC up to first disease progression. OS was

calculated as the duration from MBC diagnosis to death. The Kaplan–Meier product-limit method was

used to estimate OS, which was compared across cohorts using a log-rank test. Multivariate Cox

regression was used to evaluate the association between baseline patient and disease characteristics

and OS.

RESULTS

Patients




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Patients in SystHERs were enrolled from June 2012 to June 2016. Among 977 patients who met eligibility

criteria, 70.1% (685/977) had HR-positive and 29.9% (292/977) had HR-negative MBC. Within the HR-

positive group, 60 (8.8%) had 1%–9% HR positivity and 550 (80.3%) had 10%–100% HR positivity; 75

(10.9%) patients were missing data for the percentage of HR positivity (Supplemental Fig. 1). At the

February 22, 2018 data cutoff date, median follow-up duration was 27.6 months from MBC diagnosis for

all patients, and 28.6 and 25.3 months in patients with HR-positive and HR-negative disease,

respectively. The most common reasons for patient discontinuation were death (HR-positive: 26.9%

[184/685] and HR-negative: 40.8% [119/292]) and sponsor decision to terminate the study (HR-positive:

54.3% [372/685] and HR-negative: 46.9% [137/292]).

When comparing patient baseline demographics and disease characteristics between the HR-positive

and HR-negative cohorts, differences were observed in race, MBC diagnosis type, proportion of visceral

disease, and metastatic site locations (Table 1). The HR-positive cohort (vs. HR-negative cohort) had a

lower proportion of black/African American patients (13.4% [92/685] vs. 20.2% [59/292]) and a higher

proportion of white patients (81.3% [557/685] vs. 71.6% [209/292]). The HR-positive cohort (vs. HR-

negative cohort) also had a lower proportion of patients with de novo MBC (46.3% [317/685] vs. 58.2%

[170/292]) and visceral disease (63.1% [432/685] vs. 74.3% [217/292]). Liver metastasis was present in

35.3% (242/685) of patients with HR-positive disease and 42.5% (124/292) of patients with HR-negative

disease. Bone metastasis was present in 55.8% (382/685) of patients with HR-positive disease and 41.4%

(121/292) of patients with HR-negative disease.

Within the HR-positive cohort, patients with low HR positivity (1%–9%) differed from those with

moderate/high HR positivity (10%–100%) in the proportion of black/African American patients (20.0%

[12/60] vs. 12.9% [71/550], respectively). Small disparities were also observed between the subgroups

with low HR positivity (1%–9%) and moderate/high HR positivity (10%–100%) in the proportions of




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patients with de novo MBC (41.7% [25/60] vs. 48.5% [267/550]), visceral disease (66.7% [40/60] vs.

62.5% [344/550]), liver metastasis (40.0% [24/60] vs. 35.6% [196/550]), and bone metastasis (50.0%

[30/60] vs. 56.7% [312/550]) (Supplemental Table 1).

In patients with HR-positive disease and HR status data available for both primary and metastatic

tumors, concordance for HR positivity between primary and metastatic tissue was 81.0% (Supplemental

Table 2A). Concordance was numerically lower in patients with low HR positivity (1%–9%) versus

moderate/high HR positivity (10%–100%) (47.4% vs. 87.1%, respectively) (Supplemental Table 2B–C). In

both HR-positive subgroups, patients with discordant HR status had HR-positive primary tumors and HR-

negative metastatic tumors more commonly (low HR positivity: 25.0%; moderate/high HR positivity:

5.6%) than the converse; i.e., HR-negative primary and HR-positive metastatic tumors (low HR positivity:

8.3%; moderate/high HR positivity: 3.1%).

Treatment patterns

At data cutoff, 97.8% (670/685) of the HR-positive cohort and 95.2% (278/292) of the HR-negative

cohort had received first-line systemic treatment for MBC. In the HR-positive cohort, the most common

regimen was HER2-targeted therapy + chemotherapy + endocrine therapy, administered to 310 (45.3%)

patients, with the sequential administration of endocrine therapy (i.e., chemotherapy induction

followed by maintenance endocrine therapy) more common than concurrent administration (34.9%

[239/685] vs. 10.4% [71/685], respectively) (Table 2). The second-most common regimen was HER2-

targeted therapy + chemotherapy without endocrine therapy, received by 247 (36.1%) patients.

Additionally, 75 (10.9%) patients received HER2-targeted therapy + endocrine therapy (no

chemotherapy), 3 (0.4%) received chemotherapy + endocrine therapy, 17 (2.5%) received endocrine

therapy alone, and 18 (2.6%) received HER2-targeted therapy alone or chemotherapy alone (no

endocrine therapy).




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Overall, 59.1% (405/685) of patients with HR-positive disease had any first-line exposure to endocrine

therapy, most frequently aromatase inhibitors (46.3% [317/685]). Endocrine therapy was administered

with HER2-targeted therapy in 56.2% (385/685) of patients, which included trastuzumab + pertuzumab

in 40.4% (277/685). Of note, 56 patients with HR-positive breast cancer progressed, withdrew, or were

lost to follow-up within 9 months on study, while 142 patients were still in the first-line treatment phase

without any endocrine treatment at data cutoff (56 of those patients were still receiving first-line

chemotherapy). As such, the number of patients planned to receive or actually administered first-line

endocrine therapy may be underestimated.

In the HR-negative cohort, the most common first-line regimen was HER2-targeted therapy +

chemotherapy (87.7% [256/292]) (Table 2). Patients with HR-positive and HR-negative disease received

HER2-targeted therapies in similar proportions (94.5% [647/685]) vs. 94.5% [276/292]), but patients

with HR-positive disease were treated with chemotherapy less commonly than those with HR-negative

disease (82.2% [563/685] vs. 91.8% [268/292]). A regimen of trastuzumab + pertuzumab + taxane (with

or without endocrine therapy) was administered to a slightly lower proportion of patients with HR-

positive than HR-negative disease (65.5% [449/685] vs. 69.2% [202/292]).

Within the HR-positive cohort, patients with tumors showing low HR positivity (1%–9%) received first-

line HER2-targeted therapy + chemotherapy + endocrine therapy at a notably lower proportion than

those with moderate/high HR positivity (10%–100%) (25.0% [15/60] vs. 49.1% [270/550]) and were less

likely to receive endocrine therapy overall (33.3% [20/60] vs. 64.2% [353/550]) (Supplemental Table 3).

Rather, patients with tumors showing low HR positivity (1%–9%) more commonly received HER2-

targeted therapy + chemotherapy without endocrine therapy compared with patients whose tumors

had moderate/high HR positivity (10%–100%) (60.0% [36/60] vs. 32.0% [176/550]).




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Patients with de novo HR-positive MBC were treated with first-line chemotherapy (86.1% [273/317] vs.

78.8% [290/368]) and/or endocrine therapy (65.6% [208/317] vs. 53.5% [197/368]) more commonly

than those with recurrent HR-positive disease (Supplemental Table 4). HER2-targeted therapy +

chemotherapy + endocrine therapy was administered to a higher proportion of patients with de novo

versus recurrent disease within the HR-positive cohort (55.2% [175/317] vs. 36.7% [135/368]), as was

the administration of trastuzumab + pertuzumab + taxane (with or without endocrine therapy; 71.0%

[225/317] vs. 60.9% [224/368]).

Among patients with HR-positive disease, use of first-line endocrine therapy was more common with

increasing age (<50 years: 56.8% [104/183], 50–69 years: 62.8% [221/352], ≥70 years: 77.4% [65/84]),

while use of chemotherapy became less common (<50 years: 90.2% [165/183], 50–69 years: 85.2%

[300/352], ≥70 years: 63.1% [53/84]). Black/African American and white patients received HER2-

targeted therapy and chemotherapy at similar rates within each HR cohort, but in patients with HR-

positive disease, use of endocrine therapy was slightly more common in black/African American

patients (68.3% [56/82] vs. 61.6% [309/502]).

Clinical outcomes

By data cutoff, 30.4% (208/685) of patients in the HR-positive cohort and 42.1% (123/292) of patients in

the HR-negative cohort had died. Estimated median OS from MBC diagnosis was longer in patients with

HR-positive disease (53.0 months) than those with HR-negative disease (43.4 months; HR 0.70, 95% CI,

0.56–0.87) (Fig. 1). A multivariate analysis adjusting for baseline patient and disease characteristics

indicated that HR-positive status is associated with better survival outcomes than HR-negative status

(Supplemental Fig. 2). Median OS in patients with low HR positive tumors (1%–9%) was shorter

compared with patients with moderate/high HR positive tumors (10%–100%) (40.1 vs. 53.8 months) and

similar to patients with HR-negative disease (43.4 months) (Fig. 2).




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In both the HR-positive and HR-negative cohorts, patients with de novo MBC had longer median OS than

those with recurrent MBC (HR-positive: de novo, not reached vs. recurrent, 45.1 months; HR-negative:

de novo, 54.6 months vs. recurrent, 30.8 months) (Fig. 3). Relative to patients 50–69 years old, patients

<50 years old at MBC diagnosis had numerically longer OS in both the HR-positive (49.3 vs. 56.8 months,

respectively) and HR-negative cohorts (42.7 vs. 54.6 months, respectively) (Supplemental Fig. 3).

Black/African American and white patients had similar median OS in the HR-positive cohort (56.8 vs.

53.0 months, respectively), but in the HR-negative cohort, black/African American patients had

numerically shorter median OS compared with white patients (36.4 vs. 46.7 months) (Supplemental Fig.

4).

Within the HR-positive cohort, patients who received any first-line endocrine therapy had a median OS

of “not reached” (95% CI, 51.7–not reached), compared with 40.1 months (95% CI, 35.9–53.0 months) in

patients who did not receive first-line endocrine therapy. Median PFS for patients in the HR-positive

cohort who received any first-line endocrine therapy was 20.4 months (95% CI, 18.4–23.3 months)

compared with 10.2 months (95% CI, 9.0–11.9 months) in patients in this cohort who did not receive

first-line endocrine therapy.

DISCUSSION

Our analysis of patients with HER2-positive MBC from the real-world SystHERs study indicated that

56.2% of patients with HR-positive disease received first-line treatment with HER2-targeted therapy +

endocrine therapy, which was commonly administered as a regimen of HER2-targeted therapy +

chemotherapy + sequential endocrine therapy (34.9% of HR-positive patients). First-line endocrine

therapy was used less commonly in patients in the HR-positive cohort who had tumors with low (1%–

9%) versus moderate/high HR positivity (10%–100%), possibly due to variable use of the revised cutoff




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from ASCO/CAP (10) for considering tumors HR-positive. Patients with HR-positive disease had longer

median OS compared with those with HR-negative disease (53.0 vs. 43.4 months), potentially reflecting

less aggressive disease in the HR-positive cohort and also possibly due to the availability of another

targeted therapy (i.e., endocrine therapy) for these patients. Survival outcomes were also better for

patients with de novo (rather than recurrent) MBC in both HR subgroups, presumably due to the lack of

acquired drug resistance due to prior adjuvant therapy.

Current ASCO guidelines for use of endocrine therapy in HR-positive MBC recommend treatment with

endocrine therapy in patients with MBC and any percentage of HR positivity (6). In patients with HER2-

positive MBC that is also HR-positive, initial first-line treatment with HER2-targeted therapy and

chemotherapy is recommended based on demonstrated benefits in PFS and OS with dual antibody

therapy, specifically pertuzumab + trastuzumab in combination with a taxane (8, 9), with the potential

use of maintenance endocrine therapy following cessation of chemotherapy (6, 14). In the present

investigation from SystHERs, we found that 65.5% of patients with HR-positive disease received

trastuzumab + pertuzumab + taxane (with or without endocrine therapy) and 69.2% of patients with HR-

negative disease also received trastuzumab + pertuzumab + taxane. ASCO guidelines further state that

for patients with HER2-positive and ER/PR-positive breast cancer, clinicians may recommend either

standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or

endocrine therapy alone (14). Such recommendations reflect evolving preferred treatment patterns in

the absence of data from randomized, double-blind, controlled trials (14), which may be due, in part, to

availability of results from prospective outcome studies such as registHER (6, 7). For example,

observations from the registHER study demonstrated that the addition of endocrine therapy to

trastuzumab + chemotherapy was associated with longer median PFS and OS compared with HER2-

targeted therapy + chemotherapy alone (7). Furthermore, there was a trend towards improved OS with

sequential use of chemotherapy + endocrine therapy versus concurrent administration (7). Despite such




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data and guidelines, in SystHERs we found that only 45.3% of patients with HR-positive, HER2-positive

MBC received first-line HER2-targeted therapy + chemotherapy + endocrine therapy (34.9% sequential,

10.4% concurrent). Most of the remaining patients received HER2-targeted therapy + chemotherapy

only (36.1%) or HER2-targeted therapy + endocrine therapy (10.9%). Overall, first-line endocrine therapy

was administered to 59.1% of patients in the HR-positive subgroup. Of note, first-line maintenance

endocrine therapy may have been underestimated due to the limited follow-up time. Additionally, as

some patients progressed prior to completing a course of first-line chemotherapy, the actual

administration of maintenance endocrine therapy may have been lower than planned administration.

It remains to be seen whether maintenance first-line endocrine therapy following pertuzumab +

trastuzumab + taxane treatment, the current standard of care, confers a survival advantage in patients

with HR-positive, HER2-positive disease. The PERTAIN study investigated first-line trastuzumab + an

aromatase inhibitor (AI) with or without pertuzumab and with or without induction chemotherapy in

patients with HER2-positive, HR-positive MBC or locally advanced breast cancer (15). Data from PERTAIN

showed that in patients who received induction chemotherapy (i.e., trastuzumab + induction

chemotherapy + AI with or without pertuzumab), PFS was similar between those who received

pertuzumab (16.89 months) and those who did not (16.85 months). For patients who did not receive

induction chemotherapy (i.e., trastuzumab + AI with or without pertuzumab), PFS was longer in patients

who received pertuzumab (21.72 months) compared with those who did not (12.45 months).

Importantly, PERTAIN was not designed to show differences between patients with and without

induction chemotherapy.

In the present study, patients with HR-positive disease and tumors with moderate/high HR positivity

exhibited longer OS than those with tumors with low HR positivity or HR-negative disease. OS did not

notably differ between patients in the low HR positivity versus HR-negative disease subgroups.




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However, it is unclear whether low versus high HR positivity are truly prognostic indicators for survival,

or if the disparities we observed result from differences in baseline characteristics or treatments

administered between the two groups. Despite ASCO/CAP recommendations that tumors with 1%–9%

HR positivity be considered HR-positive with regard to disease management (10), our analysis of data

from SystHERs suggest that these patients may have different treatment patterns compared with the

10%–100% HR-positive group. Only 33.3% of patients with 1%–9% HR-positive disease received

endocrine therapy, versus 64.2% of patients with tumors with 10%–100% HR positivity. Data from

recent retrospective studies in early breast cancer suggest that patients with primary breast tumors

expressing ER in 1%–9% of cells may derive limited or no benefits from endocrine therapy (16, 17).

While the number of patients with 1%–9% HR positivity in SystHERs (n=60) is too limited to assess the

association of specific treatment regimens with clinical outcomes, future studies should investigate

whether low HR positivity in patients with HER2-positive MBC is predictive of clinical benefits from

endocrine therapy.

Among patients with HR-positive disease stratified by MBC diagnosis type, age, or race, those with de

novo MBC, older patients, and black/African American patients received regimens containing first-line

endocrine therapy more commonly than those with recurrent MBC, younger patients, and white

patients, respectively. Chemotherapy was also more commonly administered to patients with de novo

(vs. recurrent) MBC, and was administered to older patients less frequently than younger patients.

Chemotherapy use was similar between black/African American and white patients. Patients with HR-

positive breast cancer had consistently longer OS than those with HR-negative cancer. This difference

may potentially be attributable, in part, to the availability of endocrine therapy for these patients as well

as in those patients with intrinsically less aggressive biology.




20

Among patients with HER2-positive MBC in the SystHERs registry, 70.1% were identified as having HR-

positive disease compared with 55.0% of patients in registHER, which enrolled patients from 2003 to

2006 (7). Statistical modeling of data from the National Cancer Institute’s Surveillance, Epidemiology,

and End Results (SEER) Program projected that the proportion of patients with HR-positive breast cancer

would increase between 2009 and 2016, particularly in younger women (18). As of 2010, data from SEER

suggested that among patients with known HR and HER2 status, 5240 of 7568 patients (69.2%) with

HER2-positive breast cancer had HR-positive status (2). This increase could potentially be due to the

ASCO/CAP-advised changes to the HR-positive cut-off criteria in 2010 (10), raising the number of

patients effectively classified as HR-positive. This increase could also potentially be due to differences in

adjuvant treatments (eg, trastuzumab) that could have influenced the natural history and characteristics

of patients who develop MBC and/or bias in the time to recurrence between HR-positive versus HR-

negative disease. Given the availability of endocrine therapies used for the treatment of HR-positive, but

not HR-negative breast cancer, such a trend may ultimately increase survival rates in patients with

breast cancer overall.

Patient sampling in the SystHERs study was methodologically rigorous, with a very low rate of refusals

over the enrollment period, and the patient population was nationally representative. Therefore, our

patient population likely provides an accurate depiction of real-world practice and treatment patterns

over the study period. Limitations of this analysis include short follow-up time in some patients,

potentially underestimating the percentage of patients with HR-positive disease who received

maintenance first-line endocrine therapy; a relatively small number of patients in the low HR-positive

subgroup; and missing percentages for HR positivity in 10.9% of patients from the HR-positive subgroup.

Furthermore, as the percentage of ER-positive or PR-positive cells was not reported for patients

considered by local investigators to have HR-negative disease, it is possible that some patients with low

HR-positivity may have been included in the HR-negative subgroup. Also, treatment decisions based on




21

aggressiveness of clinical features and patient performance statuses could have introduced selection

bias in outcomes associated with specific treatments. For example, among patients receiving induction

chemotherapy, those with more aggressive disease might progress and move on to other chemotherapy

regimens rather than sequential endocrine therapy. This removes such patients with aggressive disease

from the group receiving sequential treatment, thereby potentially selecting for better outcomes in the

patients who remain.

In summary, data from SystHERs suggest that some patients with HR-positive, HER2-positive breast

cancer in the real world may be undertreated despite real world experience that the addition of

maintenance endocrine therapy to maintenance HER2-targeted therapy, following HER2-targeted

therapy + chemotherapy, is associated with improved survival. Furthermore, we observed that most

patients’ tumors showing low HR-positivity were not administered endocrine therapy, potentially

influenced by studies indicating limited benefits for endocrine therapy in this population. To optimize

disease management in the potentially growing number of patients with HR-positive, HER2-positive

breast cancer, future studies should assess 1) the efficacy of various treatment and sequencing

combinations with endocrine therapy, including whether the increased administration of first-line HER2-

targeted therapy, chemotherapy, and maintenance endocrine therapy improves outcomes in patients

with HR-positive, HER2-positive MBC in the real world; and 2) the utility of endocrine therapy in the

population of patients with tumors expressing low HR-positivity.

ACKNOWLEDGMENTS

The authors are grateful to the patients, families, and investigators who participated in SystHERs. We

would also like to thank: Musa Mayer for her work as part of the SystHERs Steering Committee; the

entire SystHERs team, including clinical operations leads Michelle Usher (F. Hoffmann-La




22

Roche/Genentech, Inc.) and Sandy Lam (F. Hoffmann-La Roche/Genentech, Inc.); Bongin Yoo (F.

Hoffmann-La Roche/Genentech, Inc.) for his contributions to the statistical analysis; Allen Lee (Everest

Clinical Research Services, Inc.) for his assistance with the statistical analysis; and Bokai Xia (F.

Hoffmann-La Roche/Genentech, Inc.) for his statistical programming expertise. Support for third-party

writing assistance was provided by Sabrina Hom, PhD, of CodonMedical, an Ashfield Company, part of

UDG Healthcare plc, and funded by F. Hoffmann-La Roche/Genentech, Inc. F. Hoffmann-La

Roche/Genentech, Inc. funded the SystHERs study and participated in the study design, data collection,

data analysis, data interpretation, and writing of this report.




23

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26

TABLES

Table 1. Baseline demographics, patient characteristics, and disease characteristics

All eligible patientsa

(N=977)

HR-positive

(n=685)

HR-negative

(n=292)

Median age at MBC diagnosis,

years (range) 56 (21–90) 57 (21–86) 56 (28–90)

Sex, n (%)

Female

Male

972 (99.5)

5 (0.5)

681 (99.4)

4 (0.6)

291 (99.7)

1 (0.3)

Race, n (%)

White

Black/African American

Asian

Other

Not reported/unknown

766 (78.4)

151 (15.5)

13 (1.3)

29 (3.0)

18 (1.8)

557 (81.3)

92 (13.4)

11 (1.6)

15 (2.2)

10 (1.5)

209 (71.6)

59 (20.2)

2 (0.7)

14 (4.8)

8 (2.7)

BMI, n (%)

<30

≥30

Missing

581 (59.5)

385 (39.4)

11 (1.1)

406 (59.3)

270 (39.4)

9 ( 1.3)

175 (59.9)

115 (39.4)

2 (0.7)

ECOG PS, n (%)

0–1

2+

Unknown/missing

825 (84.4)

75 (7.7)

77 (7.9)

573 (83.6)

51 (7.4)

61 (8.9)

252 (86.3)

24 (8.2)

16 (5.5)

Menopausal status, n (%)

Postmenopausal

Premenopausal

Unknown

n=972

676 (69.5)

223 (22.9)

73 (7.5)

n=681

481 (70.6)

158 (23.2)

42 (6.2)

n=291

195 (67.0)

65 (22.3)

31 (10.7)

MBC diagnosis typeb, n (%)

De novo

Recurrent

487 (49.8)

490 (50.2)

317 (46.3)

368 (53.7)

170 (58.2)

122 (41.8)

Visceral diseasec, n (%) 649 (66.4) 432 (63.1) 217 (74.3)

Number of metastatic sites at

MBC diagnosis, n (%)

1

2

≥3

417 (42.7)

258 (26.4)

302 (30.9)

286 (41.8)

184 (26.9)

215 (31.4)

131 (44.9)

74 (25.3)

87 (29.8)

Selected metastatic sites, n (%)

Bone

503 (51.5)

382 (55.8)

121 (41.4)




27

Liver

Lung

Brain/CNS

366 (37.5)

310 (31.7)

87 (8.9)

242 (35.3)

207 (30.2)

57 (8.3)

124 (42.5)

103 (35.3)

30 (10.3) aSome baseline characteristics for all eligible patients in the SystHERs study were also reported by Hurvitz et al

(age, race, BMI, ECOG PS, MBC diagnosis type, and number of metastatic sites at diagnosis) (12) and Tripathy et al

(visceral disease and selected metastatic sites) (13).

bDe novo (as opposed to recurrent) MBC indicates <90 days between early breast cancer and MBC diagnoses.

cIncludes nonhepatic abdominal, ascites, central nervous system, liver, lung, or pleural effusion sites of metastasis.

Abbreviations: BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; HR,

hormone receptor; MBC, metastatic breast cancer.




28

Table 2. First-line HER2-targeted therapy by HR status

HR-positive

(n=685)

HR-negative

(n=292)

Systemic therapya by patients with any first-line exposure, n (%)

HER2-targeted therapy

Trastuzumab

Trastuzumab + pertuzumab

Trastuzumab without pertuzumab

T-DM1

Lapatinib

647 (94.5)

622 (90.8)

496 (72.4)

126 (18.4)

46 (6.7)

23 (3.4)

276 (94.5)

264 (90.4)

215 (73.6)

49 (16.8)

25 (8.6)

18 (6.2)

Chemotherapyb

Taxane or epothilone

Platinum compound

Antimetabolite

Vinca derivative

563 (82.2)

516 (75.3)

67 (9.8)

22 (3.2)

19 (2.8)

268 (91.8)

235 (80.5)

42 (14.4)

21 (7.2)

20 (6.8)

Endocrine therapyb

Aromatase inhibitor

Tamoxifen

Fulvestrant

405 (59.1)

317 (46.3)

76 (11.1)

46 (6.7)

12 (4.1)

10 (3.4)

3 (1.0)

1 (0.3)

HER2-targeted therapy combinationsa by patients with any first-line exposure, n (%)

Trastuzumab + chemotherapy

Trastuzumab + endocrine therapy 539 (78.7) 370 (54.0)

255 (87.3) 12 (4.1)

Trastuzumab + pertuzumab + chemotherapy

Trastuzumab + pertuzumab + endocrine therapy

463 (67.6)

277 (40.4)

213 (72.9)

10 (3.4)

Trastuzumab without pertuzumab + chemotherapy

Trastuzumab without pertuzumab + endocrine therapy 76 (11.1) 93 (13.6)

42 (14.4) 2 (0.7)

Systemic therapy regimens, n (%) (mutually exclusive)

HER2-targeted therapy + chemotherapy + endocrine therapy

Concurrent

Sequential

310 (45.3)

71 (10.4)

239 (34.9)

10 (3.4)

1 (0.3)

9 (3.1)

HER2-targeted therapy + chemotherapy only 247 (36.1) 256 (87.7)

HER2-targeted therapy + endocrine therapy only 75 (10.9) 2 (0.7)

Chemotherapy + endocrine therapy only 3 (0.4) 0

Endocrine therapy only 17 (2.5) 0

HER2-targeted therapy only 15 (2.2) 8 (2.7)

Chemotherapy only 3 (0.4) 2 (0.7) aTreatments are not mutually exclusive.

bMost commonly used therapies are shown.

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor; T-DM1, trastuzumab

emtansine.




29

FIGURES

Figure 1. Overall survival by HR status.

Abbreviations: CI, confidence interval; HR, hormone receptor; OS, overall survival.

Figure 2. Overall survival by 1%–9% vs. 10%–100% HR positivity in patients with HR-positive, HER2-

positive MBC.

Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hormone receptor;

MBC, metastatic breast cancer; OS, overall survival.

Figure 3. Overall survival by HR status and de novo vs. recurrent MBC in patients with HER2-positive

disease.

Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hormone receptor;

MBC, metastatic breast cancer; NR, not reached; OS, overall survival.













Published OnlineFirst November 26, 2019.Clin Cancer Res Melody Cobleigh, Denise Yardley, Adam M Brufsky, et al. Hormone Receptor Status From SystHERsPatients with HER2-Positive Metastatic Breast Cancer by Baseline Characteristics, Treatment Patterns, and Outcomes in

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